CYP1A1 GENE REGULATION AND HUMAN CANCER

我们实验室的一个主要目标是阐明 人细胞色素P450、细胞色素P1A1与肺癌的关系这种蛋白质 CYP1A1基因产物及其相关的催化活性， 包括芳基(或芳香族)碳氢羟基酶(AHH) 与众多新陈代谢的激活密切相关 发现的致癌多环芳烃(PAHs) 香烟烟雾和其他环境污染物高度活跃 中间体。许多研究已经报道了显著的相关性。 这种表型与肺癌易感性增加之间的关系 吸烟者。 1)确定负责的分子机制 人细胞色素P1A1基因的表达。CYP1A1基因的诱导 表达是通过ah受体(AhR)的作用来调节的。 至少有五个AhR的候选结合位点在 的调节区，我们进行了一项 对每个模块进行详细的功能分析。通过这个程序，我们已经确定了 CYP1A1基因表达的独特机制。 2)编码该基因的新多态的鉴定 AH受体(AhR)的配体结合亚基。我们已经承诺 识别与基因相关的基因内的多态的任务 细胞色素P1A1基因表达的调控。我们最近发表了 一个MspI限制性片段长度多态性的鉴定 (RFLP)。来自年龄、种族和性别的DNA与对照组和 对经组织学证实的肺癌患者进行检查以确定 新获得的遗传标记在两个群体中的出现频率 人口。在67%的对照组中存在多态等位基因 人口和缺失率为33%。在肺癌人群中， 53%的受检者存在多态等位基因， 在剩下的47%中没有。我们已经确定，如果没有 等位基因多态是肺癌增加的一个相关因素 风险(OR 2.45)。初步数据还表明，有性别和 多态频率的种族差异。进一步 对这种多态的表征正在进行中。

A major goal of our laboratory has been the elucidation of the role of the human cytochrome P450, CYP1A1, in lung carcinogenesis. The protein product of the CYP1A1 gene and its associated catalytic activities, including aryl (or aromatic) hydrocarbon hydroxylase (AHH), are known to be intimately associated with the metabolic activation of numerous procarcinogenic polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke and other environmental pollutants to highly reactive intermediates. Numerous studies have reported a significant correlation between this phenotype and an enhanced susceptibility to lung cancer in cigarette smokers. 1) Determination of the molecular mechanisms responsible for expression of the human CYP1A1 gene. Induction of CYP1A1 gene expression is mediated through the action of the Ah receptor (AhR). There are at least five candidate binding sites for the AhR within the regulatory region of the CYP1A1 gene, and we have carried out a detailed functional analysis of each. By this procedure we have identified a unique mechanism for the expression of the CYP1A1 gene. 2) Identification of novel polymorphisms of the gene encoding the ligand-binding subunit of the Ah receptor (AhR). We have undertaken the task of identifying polymorphisms within genes associated with the regulation of CYP1A1 gene expression. We recently published the identification of an MspI restriction fragment length polymorphism (RFLP) of the AhR. DNAs from age, race, and sex matched controls and histologically confirmed lung cancer patients were examined to determine the frequency of the newly acquired genetic marker within the two populations. The polymorphic allele was present in 67% of the control population and absent in 33%. In the lung cancer population, the polymorphic allele was present in 53% of the individuals examined and absent in the remaining 47%. We have determined that the absence of the polymorphic allele is a factor associated with increased lung cancer risk (OR 2.45). Preliminary data also suggest that there are gender and race differences in the frequency of the polymorphism. Further characterization of this polymorphism is in progress.